Cardiovascular disease is the leading cause of death in United States. However, the molecular events that control heart development and cardiac function are not fully understood. MicroRNAs (miRNAs) are a class of small regulatory RNA molecules found in most organisms. Emerging evidence has established that miRNAs play important regulatory roles, mainly by degrading target messenger RNAs (mRNAs) and/or inhibiting translation of protein-coding mRNAs in a variety of biological processes, including cell proliferation, differentiation and survival. miRNAs are also implicated in many human diseases, including cardiovascular disease. The discovery of miRNAs and their potential biological functions in regulating gene expression opened a completely new field to investigate how miRNAs participate in ?classical? gene expression pathways. To date, more than 2,000 miRNAs have been identified in humans; however, the molecular mechanisms and the in vivo functions of most miRNAs remain unknown. The overall goal of this study is to define the biological function and the molecular mechanisms of miRNAs in the heart. Our central hypothesis is that miRNAs are components of the molecular circuitry that controls cardiac gene expression and function. More specifically, we will test our hypothesis that the Trbp-miR-208a pathway regulates cardiac function is a context-dependent manner. We present three integrative aims to test our hypothesis: Aim #1. What is the function of Trbp in the heart under pathophysiological stresses? Aim #2. How is the specificity of Trbp function in the miRNA pathway defined in the heart? Aim #3. What is the role of miR-208a in the heart and how does it work? Our studies will provide important insights into the molecular mechanisms by which miRNAs control mammalian heart development, function and cardiac gene expression. The molecular strategies we uncover in these studies will help define the ontogenesis of heart failure with potential broader implications for understanding the pathophysiology of cardiac disease in humans.